The RNA picornaviruses have evolved wonderfully robust and effective mechanisms to express their[unreadable] proteins and override host defenses. Novel internal ribosomal entry sites (IRESs) allow these genomes to[unreadable] bypass normal translational requirements for 5' cap structures and efficiently lure the ribosomes into viral[unreadable] instead of cellular pathways. The captured ribosomes pass down a single, long open reading frame (ORF),[unreadable] creating polyproteins that are in reality, tandem linkages of all structural and enzymatic units necessary for[unreadable] rapid and virulent infection. Individual protein fragments are liberated co-translationally and posttranslationally[unreadable] in an elaborate proteolytic cascade that is a defining feature of this family. The molecular[unreadable] biology of picornaviruses, and in particular that of poliovirus and the closely related human rhinovirus, is[unreadable] perhaps one of the best understood and most thoroughly accessible experimental systems in all of biology.[unreadable] Basic mechanisms of IRES translation, protein processing or genome replication have been under[unreadable] investigation for decades and there are superb molecular and recombinant tools available for the study of[unreadable] every aspect of the virus lifecycle. The focus of this project is the way in which the human rhinoviruses can[unreadable] seditiously subvert a cell's innate immunity traps, crippling the capacity of that cell to trigger an alarm or[unreadable] altering the nature of the alarm itself. The molecular battleground in that first infected cell, pits two key viral[unreadable] proteases, 2Apro and 3Cpro, enzymes strategically honed by evolution for this particular purpose, against[unreadable] cellular defenses that may vary significantly according to cell-type, cell-cycle, host genetics, immune history[unreadable] and current medical predisposition. We propose that substantially different disease phenotypes can be[unreadable] triggered at their core, by the ability or inability of these proteases to shutoff of crucial cellular transcription[unreadable] and translational processes. Every subsequent immune and disease response is consequent to this[unreadable] outcome. At the ultimate molecular level, the activities of these proteases instigate the cascade of events[unreadable] that set off or prevent an episode of disease. The experiments in this project will examine the cleavage[unreadable] processes and molecular consequences by which rhinovirus infection inactivates cytoplasmic-nuclear[unreadable] transport, thus crippling the ability of the cell to carry out mRNA transcription, or cap-dependent translation.[unreadable] They will determine whether an unconditional viral-induced shutoff of nuclear transport is necessary to allow[unreadable] viral replication and cell lysis. Or, under conditions when these processes are only partially effective, whether[unreadable] a host-induced up-regulation of innate triggers then quickly escalates into a full-blown immune response, that[unreadable] may or may not be inappropriate for the extent and severity of actual infection. The project will also examine[unreadable] host shutoff activities are ubiquitous and similar in multiple human cell types, or are modulated by the[unreadable] genetics and/or innate immunity status of the cultures and the genotype of virus.